The overall goal of this project is a better understanding of the mechanisms of cell entry and spread by polyoma virus. This virus infects and transforms rodent cells in culture. When inoculated into newborn mice, it spreads rapidly and induces a wide array of tumors. The pathway and mechanisms by which the virus infects cells will be studied in culture using electron microscopy and deconvolution fluorescence microscopy along with various immunological and biochemical methods. Specific aims are directed to identifying the mode of internalization, and the pathway of entry into the nucleus. Mutant viruses with defects in the structural proteins that affect entry will be characterized. We have identified an inbred mouse strain which is highly resistant to polyoma infection. The genetic and physiological bases for this host resistance will be investigated in crosses with susceptible mice, and by use of cell cultures derived from the resistant mice. The final goal of this line of investigation is the identification and understanding of the mode of action of the host resistance gene which blocks virus spread. We will also attempt to isolate polyoma virus from wild house mice and confirm the presence or absence of those determinants identified in laboratory strains which confer pathogenic properties to the virus.